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Chemistry. 2018 Apr 25;24(24):6334-6338. doi: 10.1002/chem.201800289. Epub 2018 Apr 6.

Transition Metal Ions Promote the Bioavailability of Hydrophobic Therapeutics: Cu and Zn Interactions with RNA Polymerase I Inhibitor CX5461.

Author information

1
Department of Chemistry, Simon Fraser University, 8888 University Dr., Burnaby, BC, V5A 1S6, Canada.
2
Department of Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Ave, Vancouver, BC, V5Z 4E6, Canada.

Abstract

Low aqueous solubility is a major barrier to the clinical application of otherwise promising drug candidates. We demonstrate that this issue can be resolved in medicinal molecules containing potential ligating groups, through the addition of labile transition-metal ions. Incubation of the chemotherapeutic CX5461 with Cu2+ or Zn2+ enables solubilization at neutral pH but does not affect intrinsic cytotoxicity. Spectroscopic and computational studies demonstrate that this arises from coordination to the pyrazine functionality of CX5461 and may involve bidentate coordination at physiological pH.

KEYWORDS:

bioinorganic; cancer; copper; nuclear magnetic resonance; zinc

PMID:
29490115
DOI:
10.1002/chem.201800289
[Indexed for MEDLINE]

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